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Biomedical subjects

Graham A MacGregor

Publications and source records attributed to Graham A MacGregor.

28 records · Page 2Linked to original sources
PubMed2004

The epithelial sodium channel in hypertension: genetic heterogeneity and implications for treatment with amiloride.

The epithelial sodium channel (ENaC) has a central role in sodium transport across membranes. It is expressed on the apical cell surface of renal tubular epithelia and also on other aldosterone-responsive epithelial cells. In the kidney, ENaC contributes to the regulation of blood pressure via changes in sodium balance and blood volume. Rare monogenetic disorders associated with hypertension have been described, such as Liddle syndrome, which gives rise to increased sodium reabsorption in the kidney via increased ENaC activity. There are many other variants in the genes encoding ENaC subunits, some of which occur with sufficient frequency as to be termed polymorphic variants. The Thr594Met polymorphism of the ENaC beta-subunit gene SCNN1B occurs exclusively in Black individuals, with a frequency of 6-8% in those with hypertension. It increases cAMP mediated ENaC sodium current in affected B lymphocytes, and has been associated with hypertension in a Black South London population. There is preliminary evidence that amiloride is effective as monotherapy in hypertensive individuals with the Thr594Met polymorphism and in patients with resistant hypertension, who have evidence of increased amiloride-sensitive sodium channel activity. If these preliminary studies are corroborated in larger studies, then amiloride may provide an important new strategy for blood pressure control in selected individuals.

Amiloride↗
PubMed2003

How far should salt intake be reduced?

The current public health recommendations are to reduce salt intake from 9 to 12 g/d to 5 to 6 g/d. However, these values are based on what is feasible rather than the maximum effect of salt reduction. In a meta-analysis of longer-term trials, we looked at the dose response between salt reduction and fall in blood pressure and compared this with 2 well-controlled studies of 3 different salt intakes. All 3 studies demonstrated a consistent dose response to salt reduction within the range of 12 to 3 g/d. A reduction of 3 g/d predicts a fall in blood pressure of 3.6 to 5.6/1.9 to 3.2 mm Hg (systolic/diastolic) in hypertensives and 1.8 to 3.5/0.8 to 1.8 mm Hg in normotensives. The effect would be doubled with a 6 g/d reduction and tripled with a 9 g/d reduction. A conservative estimate indicates that a reduction of 3 g/d would reduce strokes by 13% and ischemic heart disease (IHD) by 10%. The effects would be almost doubled with a 6 g/d reduction and tripled with a 9 g/d reduction. Reducing salt intake by 9 g/d (eg, from 12 to 3 g/d) would reduce strokes by approximately one third and IHD by one quarter, and this would prevent approximately 20 500 stroke deaths and 31 400 IHD deaths a year in the United Kingdom. The current recommendations to reduce salt intake from 9 to 12 g/d to 5 to 6 g/d will have a major effect on blood pressure and cardiovascular disease but are not ideal. A further reduction to 3 g/d will have a much greater effect and should now become the long-term target for population salt intake worldwide.

Adult↗
PubMed2003

Contrasting associations between aldosterone synthase gene polymorphisms and essential hypertension in blacks and in whites.

BACKGROUND: Genetic variability in the gene for aldosterone synthase--a key enzyme in the production of aldosterone--can affect sodium homeostasis and thereby blood pressure. The possibility of impaired aldosterone production for the development of hypertension is of particular relevance in black Afro-Caribbeans exposed to a high dietary sodium intake. OBJECTIVES: To compare the frequency of three variants (-344C/T, intron 2 conversion, and the K173R polymorphism) of the aldosterone synthase gene in blacks and whites, and to determine any association of the variants with hypertension. DESIGN AND METHODS: We made case-control comparisons of the three gene variants in relation to ethnic background and to essential hypertension in 193 white (51% hypertensive) and 245 black individuals (59% hypertensive) living in south London. RESULTS: The frequency of each of the variants was significantly different between the two ethnic groups. The T and the K alleles were more frequent in the black participants (79 compared with 50% for the -344T allele and 81 compared with 50% for K173 allele), whereas the frequency of the intron 2 conversion allele was much lower in that group (8 compared with 38%). None of these variants was associated with essential hypertension in the black participants. In contrast, in the white participants there was a significant and graded association between the intron 2 conversion allele and essential hypertension (odds ratio 1.86, 95% confidence interval 1.16 to 2.98; = 0.01). Moreover, among the white population, the presence of homozygosity both of the T allele and of the intron 2 conversion alleles was associated with a much greater frequency of hypertension (71 compared with 43%; chi(2) = 0.03). CONCLUSIONS: The contrasting associations between these variants and essential hypertension do not necessarily exclude the possibility that other, as yet undefined, variants of the aldosterone synthase gene could be linked with hypertension in black people. Nonetheless, the strong association between the intron 2 conversion allele and essential hypertension in the white population reinforces the view that the increased blood pressure may be due, at least in part, to abnormal expression of enzymes involved in the metabolism of adrenal mineralocorticoids.

Adenine↗
PubMed2003

Salt, blood pressure and the renin-angiotensin system.

Much evidence from epidemiological, migration, intervention, animal and genetic studies suggests that salt intake plays an important role in regulating blood pressure (BP). At the same time, many clinical trials have shown that reducing salt intake lowers BP. However, the magnitude of the fall in BP for a given reduction in salt intake varies with age, ethnic group and BP levels. This difference has been suggested to be related to the responsiveness of the renin-angiotensin system (RAS). However, the sympathetic nervous system, the kallikrein-kinin system, the nitric oxide system, and many eicosanoids may also play a role. In this article, we address the important role of the RAS in determining the fall in BP with salt reduction.

Animals↗
PubMed2002

Urinary protein and essential hypertension in black and in white people.

The objectives of this work were to examine the association between urinary protein and blood pressure and to compare the pattern of urinary protein excretion with essential hypertension in people of European origin (whites) and in people of African or African-Caribbean origin (blacks) living in southwest London, United Kingdom. In the groups as a whole, there were no significant differences in total urinary protein excretion between blacks and whites (geometric means [95% CI]: 94.0 [85.9 to 102.9] mg/24h for the blacks [n=151] and 102.1 [96.1 to 108.4] mg/24h for the whites [n= 219]). There were also no significant differences between blacks and whites in urinary albumin (6.5 [4.9 to 8.5] mg/24h for the blacks [n=97] and 7.1 [5.6 to 9.0] mg/24h for the whites [n=123]). In both groups, those with essential hypertension displayed a significantly raised urinary protein excretion (1.21-fold higher for the blacks and 1.19-fold higher for the whites) and albumin excretion (1.69-fold higher for the blacks and 2.40-fold higher for the whites). Urinary transferrin excretion measured in a subgroup of 67 subjects was also raised in those with essential hypertension (3.22-fold higher in the blacks and 2.76-fold higher in the whites). Examination of urinary proteins by SDS-PAGE did not identify any pattern consistent with a reduction in renal tubular protein reabsorption in those with essential hypertension. These results suggest that the increase in protein excretion in essential hypertension could be due, at least in part, to an increase in glomerular protein ultrafiltration.

Adult↗
PubMed2002

Amiloride, a specific drug for hypertension in black people with T594M variant?

The T594M polymorphism of the epithelial sodium channel is found in approximately 5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle's syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89+/-3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91+/-4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8+/-4/2 mm Hg (systolic, P<0.05; diastolic, P<0.01). On restarting amiloride, blood pressure was again controlled to 140/88+/-6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.

Aldosterone↗
PubMed2002

The frequent need for three or more drugs to treat essential hypertension. What evidence for optimal combinations?

Treatment of high blood pressure (BP) reduces the risk of death and morbidity from stroke and coronary heart disease. There is accumulating evidence from large outcome studies that support a move towards lower treatment targets in hypertensives, particularly for those with concomitant risk factors or evidence of established target organ damage. At present, the achieved rates for BP control in the UK are very poor. Amongst the many possible reasons for poor BP control is the under utilisation of effective drug combinations. This article addresses the rationale for two and three drug combination therapy in hypertension and reviews the trial evidence for efficacy of combinations.

Antihypertensive Agents↗
PubMedDate not supplied

Salt in food.

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Cardiovascular Diseases↗